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Tag: Cell (journal)

  • Common immune cells can prevent intestinal healing

    Common immune cells can prevent intestinal healing

    Newswise — B cells are critical to the proper functioning of the immune system. However, researchers at Karolinska Institutet have shown that they can sometimes do more harm than good, as their numbers greatly increase after bowel damage, preventing the tissue from healing. The results, which are presented in the journal Immunity, can be of significance to the treatment of inflammatory bowel disease.

    B cells are a type of white blood cell that have an important function in the immune system, in part by producing the antibodies that attack bacteria and viruses. Previous research has shown that people with chronic inflammatory bowel disease (IBD), such as Crohn’s disease or ulcerative colitis, have many more B cells in their intestines than healthy individuals. It has therefore been proposed that B cells might affect the severity of these diseases. Researchers at Karolinska Institutet in Sweden have now tried to discover if, and if so how, B cells contribute to IBD.

    Sharp increase during healing

    “We’ve been able to show that the B cell population increases sharply in the colon during the healing of colonic lesions, and that these cells mainly accumulate in areas where the damage is severe,” says principal investigator Eduardo Villablanca, associate professor at the Department of Medicine (Solna), Karolinska Institutet. “This prevents, in turn, the interaction between two other cell types – stromal and epithelial cells – which is needed for the tissue to heal.”

    The researchers studied an experimental model of colitis and tissue from patients with ulcerative colitis, using a range of methods to analyse cell populations. Focusing particularly on how B cells affect healing in the intestinal mucosa, they found that mice lacking B cells recovered much more quickly after bowel damage than regular mice. The finding that the B cells seem to do more harm than good in colonic inflammation can be of significance to the treatment of IBD.

    Drugs that affect B cells

    “There are already approved drugs that affect the B cell response and that are used for other diseases,” says Gustavo Monasterio, postdoc in Dr Villablanca’s research group at Karolinska Institutet and one of the leading authors. “We now want to test if depleting B cells at specific time windows could also work with IBD. We also need to find out if the accumulation of B cells can have a long-term beneficial effect, such as by changing the composition of bacteria in the gastrointestinal tract.”

    The study was supported by grants from the Swedish Research Council, the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation (the Wallenberg Academy Fellow programme) and the German research foundation DFG. Eduardo Villablanca has received research grants from the pharmaceutical company F. Hoffmann-La Roche and co-author Camilla Engblom is scientific consultant for the biotech company 10X Genomics Inc. Julio Saez-Rodriguez receives funding from Glaxo Smith Kline and Sanofi and consultancy fees from Travere Therapeutics.

    Publication: “B cell expansion hinders the stroma-epithelium regenerative crosstalk during mucosal healing”. Annika Frede, Paulo Czarnewski, Gustavo Monasterio, Kumar P. Tripathi, David A Bejarano, Ricardo O. Ramirez Flores, Chiara Sorini, Ludvig Larsson, Xinxin Luo, Laura Geerlings, Claudio Novella-Rausell, Chiara Zagami, Raoul Kuiper, Rodrigo A Morales, Francisca Castillo, Matthew Hunt, Livia Lacerda Mariano, Yue O. O. Hu, Camilla Engblom, Ana-Maria Lennon-Dumenil, Romy Mittenzwei, Nadine Hövelmeyer, Joakim Lundeberg, Julio Saez-Rodriguez, Andreas Schlitzer, Srustidhar Das, Eduardo J. Villablanca. Immunity, online 2 December 2022, doi: 10.1016/j.immuni.2022.11.002.

    Karolinska Institute

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  • Human evolution wasn’t just the sheet music, but how it was played

    Human evolution wasn’t just the sheet music, but how it was played

    Newswise — DURHAM, N.C. — A team of Duke researchers has identified a group of human DNA sequences driving changes in brain development, digestion and immunity that seem to have evolved rapidly after our family line split from that of the chimpanzees, but before we split with the Neanderthals.

    Our brains are bigger, and are guts are shorter than our ape peers.

    “A lot of the traits that we think of as uniquely human, and human-specific, probably appear during that time period,” in the 7.5 million years since the split with the common ancestor we share with the chimpanzee, said Craig Lowe, Ph.D., an assistant professor of molecular genetics and microbiology in the Duke School of Medicine.

    Specifically, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced like hackers, regulate genes. They are the switches that tell nearby genes when to turn on and off. The findings appear Nov.23 in the journal CELL.

    The rapid evolution of these regions of the genome seems to have served as a fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences developed into regulatory regions, and they were more finely tuned to adapt to environmental or developmental cues. By and large, those changes were advantageous to our species.

    “They seem especially specific in causing genes to turn on, we think just in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way,” Lowe said.

    A lot of this genomic innovation was found in brain development and the GI tract. “We see lots of regulatory elements that are turning on in these tissues,” Lowe said. “These are the tissues where humans are refining which genes are expressed and at what level.”

    Today, our brains are larger than other apes, and our guts are shorter. “People have hypothesized that those two are even linked, because they are two really expensive metabolic tissues to have around,” Lowe said. “I think what we’re seeing is that there wasn’t really one mutation that gave you a large brain and one mutation that really struck the gut, it was probably many of these small changes over time.”

    To produce the new findings, Lowe’s lab collaborated with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology to tap their expertise. Reddy’s lab is capable of looking at millions of genetic switches at once and Silver is watching switches in action in developing mouse brains.

    “Our contribution was, if we could bring both of those technologies together, then we could look at hundreds of switches in this sort of complex developing tissue, which you can’t really get from a cell line,” Lowe said.

    “We wanted to identify switches that were totally new in humans,” Lowe said. Computationally, they were able to infer what the human-chimp ancestor’s DNA would have been like, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genome sequences of these other post-chimpanzee relatives thanks to databases created from the pioneering work of 2022 Nobel laureate Svante Pääbo.

    “So, we know the Neanderthal sequence, but let’s test that Neanderthal sequence and see if it can really turn on genes or not,” which they did dozens of times.

    “And we showed that, whoa, this really is a switch that turns on and off genes,” Lowe said. “It was really fun to see that new gene regulation came from totally new switches, rather than just sort of rewiring switches that already existed.” 

    Along with the positive traits that HAQERs gave humans, they can also be implicated in some diseases.

    Most of us have remarkably similar HAQER sequences, but there are some variances, “and we were able to show that those variants tend to correlate with certain diseases,” Lowe said, namely hypertension, neuroblastoma, unipolar depression, bipolar depression and schizophrenia. The mechanisms of action aren’t known yet, and more research will have to be done in these areas, Lowe said.

    “Maybe human-specific diseases or human-specific susceptibilities to these diseases are going to be preferentially mapped back to these new genetic switches that only exist in humans,” Lowe said.

    Support for the research came from National Human Genome Research Institute – NIH (R35-HG011332), North Carolina Biotechnology Center (2016-IDG-1013, 2020-IIG-2109), Sigma Xi, The Triangle Center for Evolutionary Medicine and the Duke Whitehead Scholarship.

    CITATION: “Adaptive Sequence Divergence Forged New Neurodevelopmental Enhancers in Humans,” Riley J. Mangan, Fernando C. Alsina, Federica Mosti, Jesus Emiliano Sotelo-Fonseca, Daniel A. Snellings, Eric H. Au, Juliana Carvalho, Laya Sathyan, Graham D. Johnson, Timothy E. Reddy, Debra L. Silver, Craig B. Lowe. CELL, Nov. 23, 2022. DOI: 10.1016/j.cell.2022.10.016

    Duke University

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  • In lung cancer, proteins may predict prognosis, improve treatment, diagnostics

    In lung cancer, proteins may predict prognosis, improve treatment, diagnostics

    Newswise — Bethesda, Md. – Lung cancer is the leading cause of cancer deaths globally and a top cause of cancer deaths in the Military Health System. However, the ability to determine which of these patients have aggressive tumors and which will respond better to certain treatments – could soon be available through the collective analysis of proteins and genomes, according to a new study published Nov. 15 in Cell Reports Medicine, led by researchers at the Uniformed Services University (USU).

    The researchers sought to make advancements in this highly lethal cancer by looking specifically at the process through which genes (DNA) are converted to the messenger transcript (RNA), in cells, thus making proteins – a process known as the Central Dogma of Molecular Biology. When things go wrong during this process, the signal can change, thus turning healthy cells into cancer. In this study, the researchers analyzed all aspects of this process by applying several large scale technologies – whole genome sequencing, RNA sequencing, and proteomic profiling – to the most common type of lung cancer, lung adenocarcinoma. Ultimately, by bioinformatics data analysis of the DNA, RNA, protein, and phosphoprotein in cells – or what they refer to as proteogenomic characterization – they were able to connect certain molecular features of tumors with patient survivability, which could help better predict a patient’s outcome and inform clinical management.

    As a result of this analysis, the researchers also suggest their findings could lead to improved diagnostics, explained Dr. Matthew Wilkerson, one of the study’s co-authors and an associate professor in USU’s Department of Anatomy, Physiology, and Genetics, and Director of the Data Science Division in USU’s Center for Military Precision Health.

    “Our results show that patient survival can be well-predicted by protein levels in tumors, which may enable molecular diagnostics in smaller biopsies and tissue available in the clinic, which are otherwise challenging,” Wilkerson said. 

    The researchers also identified new tumor characteristics related to immune cells and regulatory networks through this proteogenomic characterization analysis. Therefore, this analysis could be used to help pinpoint which tumors may respond best to certain immunotherapies, thus improving patient treatment outcomes, Wilkerson said. 

    Furthermore, the analysis uncovered an entirely new molecular subtype of lung cancer. While previous studies have characterized lung cancer in those who are current smokers and those who have never smoked, this study found a third group, which turned out to be dominated by structural alterations – the disorganized genome – and former smokers. Ultimately, this suggests that not only if you smoked, but when you smoked affects the type of tumor you develop.

    The study, “Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants and therapeutically-relevant pathways,” was part of the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) network, a collaboration that launched in 2016 in response to the White House’s Cancer Moonshot initiative. APOLLO is led by USU’s Murtha Cancer Center (MCC)/Research Program (MCCRP), and is a collaboration between the National Cancer Institute, the Department of Defense, and the Department of Veterans Affairs, and is aimed at incorporating proteogenomics into patient care.

    Through APOLLO, additional studies are underway, using proteogenomics to analyze all aspects of the Central Dogma of Molecular Biology in hopes of improving care for many other forms of cancer. 

    “This work is significant because these are novel findings that have been identified through using multiple molecular platforms looking at DNA, RNA, and protein expression on a highly characterized lung adenocarcinoma sample collection that have led to a new understanding of both the biology of lung adenocarcinoma as well as potential therapeutic targets for the disease,” said Dr. Craig Shriver, co-author on the study and director of USU’s MCCRP.

    “A unique strength of this study is the comprehensive clinical data and follow-up from a U.S. cohort,” added Dr. Robert Browning, co-author on the study and a professor of Medicine at USU. “By avoiding potentially wide variations in medical practice with predominantly international cohorts we greatly increased confidence in the survival and outcome results for the study,” Browning said.

    “It was the combination of this exceptional clinical data to the unparalleled array of multi-omic analysis that led to one of the major findings of the study,” Browning said. “This discovery of a new subtype of lung adenocarcinoma, associated with former smokers that are often excluded from current lung cancer screening criteria, yet with some of the least treatable lung adenocarcinoma mutations and very poor survival, may provide broad translational applications in potential prevention pathway targets, screening markers and precision treatment in the very near future.”

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    About the Uniformed Services University of the Health Sciences: The Uniformed Services University of the Health Sciences, founded by an act of Congress in 1972, is the nation’s federal health sciences university and the academic heart of the Military Health System. USU students are primarily active-duty uniformed officers in the Army, Navy, Air Force and Public Health Service who receive specialized education in tropical and infectious diseases, TBI and PTSD, disaster response and humanitarian assistance, global health, and acute trauma care. USU also has graduate programs in oral biology, biomedical sciences and public health committed to excellence in research. The University’s research program covers a wide range of areas important to both the military and public health. For more information about USU and its programs, visit www.usuhs.edu.

    Uniformed Services University of the Health Sciences (USU)

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  • Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

    Defect in Gene Caused Massive Obesity in Mice Despite Normal Food Intake

    Newswise — DALLAS – Oct. 28, 2022 – A faulty gene, rather than a faulty diet, may explain why some people gain excessive weight even when they don’t eat more than others, UT Southwestern researchers at the Center for the Genetics of Host Defense have discovered.

    The findings, published in Cell Metabolism, describe how a defect in a gene called Ovol2 caused mice with normal activity levels and food intake to become obese as they reached adulthood due to problems generating body heat. If the same holds true in humans, who share a nearly identical gene and its protein product, the findings could eventually help identify potential treatments for obesity.

    “Most cases of obesity are caused by overeating or by lack of physical activity, but our research has shown that a mutation of a little-studied gene called Ovol2 causes massive obesity – due solely to a defect in thermogenesis, or heat production,” said study leader Zhao Zhang, Ph.D., Assistant Professor of Internal Medicine who co-led this study with Nobel Laureate Bruce Beutler, M.D., Professor of Immunology and Director of the Center for the Genetics of Host Defense.

    About 42% of people in the U.S. are obese, a condition that drives up the risk of many other health problems including heart disease, stroke, Type 2 diabetes, and certain types of cancer. Although researchers agree obesity appears to stem from an interplay between a person’s genes and his or her environment, the genes that play important roles in the most common forms of obesity aren’t well understood, and the most famous obesity mutations in mice and humans cause a voracious appetite.

    To learn more about basic mechanisms of obesity, Drs. Zhang and Beutler and their colleagues used a chemical to generate random mutations in the DNA of mice. In a particular family of mice, obesity began at about 10 weeks of age – young adulthood for the rodents – and continued until the animals were massively overweight. The researchers identified the responsible mutation in a gene called Ovol2.

    “No one had associated this gene with obesity before,” Dr. Beutler said, “because it’s essential for life. The mutation we created was mild enough to allow survival but damaging enough to reveal a striking metabolic defect.”

    The obese mice experienced a 556% increase in fat weight, accompanied by a 20% reduction in lean weight, compared to littermates who had not undergone mutagenesis. Experiments showed the obese animals weren’t able to maintain their core body temperature when exposed to cold, which appeared to result from an inability to effectively use a type of tissue called brown fat, the primary function of which is to generate heat. Further tests suggested that the healthy Ovol2 gene suppressed development of white fat, the main tissue responsible for energy storage.

    When the researchers overexpressed the normal Ovol2 protein, they found that animals gained far less weight than wild-type controls in mice fed a high-fat diet. The authors said these findings suggest Ovol2 is a key player in energy metabolism – which probably holds true for humans since the human Ovol2 protein is very similar to the mouse version. Eventually, said Dr. Zhang, doctors may be able to treat obesity by giving patients drugs that drive up Ovol2 function.

    Drs. Beutler and Zhang are inventors on a patent related to these findings.

    UT Southwestern is a Nutrition Obesity Research Center, one of 12 in the nation funded by the National Institutes of Health and the only one in Texas. The Center supports work by more than 150 UT Southwestern scientists to investigate the causes, prevention, and treatment options for obesity.

    Dr. Beutler is a Regental Professor who holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. He received the 2011 Nobel Prize in Physiology or Medicine for his discovery of how the innate immune system is activated.

    Other UTSW researchers who contributed to this study include Yiao Jiang, Lijing Su, Sara Ludwig, Xuechun Zhang, Miao Tang, Xiaohong Li, Priscilla Anderton, Xiaoming Zhan, Mihwa Choi, Jamie Russell, Chun-Hui Bu, Stephen Lyon, Darui Xu, Sara Hildebrand, Lindsay Scott, Jiexia Quan, Rochelle Simpson, Qihua Sun, Baifang Qin, Tiffany Collie, Meron Tadesse, and Eva Marie Y. Moresco.

    This work was supported by the National Institutes of Health (K99 DK115766, R00 DK115766, R01 AI125581, and U19 AI100627) and the Lyda Hill Foundation.

    About UT Southwestern Medical Center

    UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 18 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,900 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits a year.

    UT Southwestern Medical Center

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  • Identity Theft the Secret of the Cat Parasite’s Success

    Identity Theft the Secret of the Cat Parasite’s Success

    Newswise — The parasite Toxoplasma is carried by a large portion of the global human population. Now a study led by researchers at Stockholm University shows how this microscopic parasite so successfully spreads in the body, for example to the brain. The parasite infects immune cells and hijacks their identity. The study is published in the scientific journal Cell Host & Microbe.

    In order to fight infections, the various roles of immune cells in the body are very strictly regulated. Scientists have long wondered how Toxoplasma manages to infect so many people and animal species and spread so efficiently.

    “We have now discovered a protein that the parasite uses to reprogram the immune system”, says Arne ten Hoeve, researcher at the Department of Molecular Biosciences, Wenner-Gren Institute at Stockholm University.

    The study shows that the parasite injects the protein into the nucleus of the immune cell and thus changes the cell’s identity. The parasite tricks the immune cell into thinking it is another type of cell. This changes the gene expression and behavior of the immune cell. Toxoplasma causes infected cells which normally should not travel in the body to move very quickly and in this way the parasite spreads to different organs.

    The phenomenon has been described as Toxoplasma turning immune cells into Trojan horses or wandering “zombies” that spread the parasite. The newly published study provides a molecular explanation for the phenomenon, and also shows that the parasite is much more targeted in its spread than previously thought.

    “It is astonishing that the parasite succeeds in hijacking the identity of the immune cells in such a clever way. We believe that the findings can explain why Toxoplasma spreads so efficiently in the body when it infects humans and animals,” says Professor Antonio Barragan, who led the study, which was carried out in collaboration with researchers from France and the USA.

    The work is published in the scientific journal Cell Host & Microbe.
    The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages. Arne L. ten Hoeve, Laurence Braun, Matias E. Rodriguez, Gabriela C. Olivera, Alexandre Bougdour, Lucid Belmudes, Yohann Couté, Jeroen P.J. Saeij, Mohamed-Ali Hakimi, Antonio Barragan DOI: 10.1016/j.chom.2022.10.001

    About the parasite Toxoplasma and the disease toxoplasmosis:

    Toxoplasmosis is probably the most common parasitic infection in humans globally. Toxoplasma also infects many animal species (zoonosis), including our pets. The WHO has estimated that at least 30% of the world’s human population is a carrier of the parasite. Studies indicate that 15-20% of the Swedish population carry the parasite (the vast majority without knowing it). The incidence is higher in several other European countries.

    Felines, not just domestic cats, have a special place in the life cycle of Toxoplasma: it is only in the cat’s intestine that sexual reproduction takes place. In other hosts, for example humans, dogs or birds, reproduction takes place by the parasite dividing.

    Toxoplasma is spread through food and contact with cats. In nature, the parasite spreads preferentially from rodents to cats to rodents and so forth. The parasites are “sleeping” in the rodent’s brain and when the cat eats the mouse, they multiply in the cat’s intestine and come out via the feces. The parasite ends up in the vegetation and when the rodent eats the vegetation it becomes infected. Humans become infected through meat consumption or through contact with cats, specifically cat feces.

    The parasite causes the disease toxoplasmosis. When a person is infected for the first time, mild flu-like symptoms occur that can resemble a cold or a flu. After the first infection phase, the parasite transitions to a “sleeping” stage in the brain and begins a chronic silent infection that can last for decades or for life. The chronic infection usually causes no symptoms in healthy individuals. Toxoplasma can, however, cause a life-threatening brain infection (encephalitis) in people with a weakened immune system (HIV, organ transplant recipients, after chemotherapy) and can be dangerous to the fetus during pregnancy. Eye infections can occur in otherwise healthy individuals.

    Stockholm University

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  • Study Identifies Key T Cells for Immunity Against Fungal Pneumonia

    Study Identifies Key T Cells for Immunity Against Fungal Pneumonia

    Newswise — Researchers at the University of Illinois College of Veterinary Medicine have demonstrated in a mouse model that a specific type of T cell, one of the body’s potent immune defenses, produces cytokines that are necessary for the body to acquire immunity against fungal pathogens. This finding could be instrumental in developing novel, effective fungal vaccines.

    Despite vaccines being hailed as one of the greatest achievements of medicine, responsible for controlling or eradicating numerous life-threatening infectious diseases, no vaccines have been licensed to prevent or control human fungal infections.

    This lack proved especially deadly during the COVID-19 pandemic. In countries where steroids were widely used to suppress inflammation of the lungs, COVID-19 patients with preexisting conditions such as uncontrolled diabetes showed a greater likelihood of developing lethal fungal infections. 

    T Cells Could Produce Protective or Pathological Response

    “A particular type of T cell [TH17 cells] that expresses GM-CSF [granulocyte-macrophage colony-stimulating factor] was linked to greater severity of illness in people infected with the virus that causes COVID-19,” said Dr. Som Nanjappa, an assistant professor of immunology at the University of Illinois.

    “Our study shows that IL-17A+ CD8+ T cell (Tc17), which also expresses GM-CSF, is necessary for mediating fungal vaccine immunity without instigating hyperinflammation. So clearly, the antigen specificity of T cells—whether they target viral vs. fungal or bacterial pathogens—has a huge impact on whether they play a protective or detrimental role.”

    The article, “GM-CSF+ Tc17 cells are required to bolster vaccine immunity against lethal fungal pneumonia without causing overt pathology,” appeared in Cell Reports on October 25. Dr. Nanjappa’s coauthors on the study are Srinivasu Mudalagiriyappa, a former graduate student now a scientist with Insmed Incorporated, a global biopharmaceutical company focused on serious and rare diseases; Jaishree Sharma, a graduate student in the Department of Pathobiology; and Miranda D. Vieson, a Clinical Associate Professor in the Department of Pathobiology as well as a boarded veterinary pathologist in the college’s Veterinary Diagnostic Laboratory.

    T Cells for Fungal Vaccine Immunity

    In the study, colonies of mice were given an experimental fungal vaccine. The mice were then exposed to virulent fungal pathogen to cause lethal pulmonary infection. Researchers could determine the necessity of GM-CSF+ Tc17 cells to mediate vaccine immunity. Further, they found that IL-1 and IL-23 cytokines are necessary for eliciting GM-CSF+ Tc17 cells to vaccine. While IL-23 is dispensable for the long-term memory homeostasis of these cells, it is essential for vaccine immunity against pulmonary fungal infection.

    This study identifies a beneficial subset of T cells for fungal vaccine immunity that bolsters efforts to develop a vaccine platform containing suitable adjuvants to potentiate such a T cell subset.

    “In line with this, we have identified a functional phenotypic marker that could be targeted to enhance this subset to augment vaccine efficacy,” said Dr. Nanjappa. He recently received NIH-R01 funding to pursue this strategy for a fungal vaccine.   

    Read the study online: https://doi.org/10.1016/j.celrep.2022.111543

    University of Illinois at Urbana-Champaign

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  • Widespread metabolic dysregulation in different organs in type 2 diabetes

    Widespread metabolic dysregulation in different organs in type 2 diabetes

    Newswise — The most typical alterations in people with type 2 diabetes are insufficient secretion of insulin and reduced sensitivity to insulin in different organs. To examine what happens in these organs when type 2 diabetes develops, the researchers in the current study have looked at proteins both in the cell islets in the pancreas where insulin is produced, and in the main tissues that insulin acts on, namely the liver, skeletal muscle, fat and blood.

    The researchers compared proteins in samples from people with type 2 diabetes, prediabetes, i.e. a stage before fully developed type 2 diabetes, and without any diabetes. The results showed far more disturbances in metabolic pathways than previously known. There was also a correlation between the alterations and the different stages of the disease.

    “We detected many protein levels that were either higher or lower than normal in tissues from people at different stages of disease. People with prediabetes displayed major alterations that are associated with inflammation, coagulation and the immune system in the pancreatic islets. In fully developed type 2 diabetes there were more widespread abnormalities, for example in lipid and glucose metabolism and in energy production in the liver, muscle and fat,” says Professor Claes Wadelius, who coordinated the study.

    The study builds on tissue samples collected from donors at different stages of disease and healthy individuals. The samples have been collected in the strategic initiative EXODIAB, which is led in Uppsala by Professor Olle Korsgren.

    Using novel techniques, the researchers could quantify thousands of proteins from each organ and therefore obtain a view of the metabolism that has not been possible before.

    “The techniques for measuring proteins have evolved rapidly in recent years and our colleagues at Copenhagen University who participated in the study are world leaders in the field,” says Dr Klev Diamanti, who performed the analyses in Uppsala together with Associate Professor Marco Cavalli and Professor Jan Eriksson.

    In summary, the findings show a highly disturbed metabolism in different pathways in examined organs and at different stages of disease. The data points to new potentially causal mechanisms of the disease, which can be further investigated in the search for new ways of preventing or treating type 2 diabetes.

    “Our results may also support the development of simple tests that can identify people at high risk of diabetes and its complications, and also guide which type of intervention is best for the individual,” says clinical diabetologist Jan Eriksson.

    Uppsala University

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  • Scientists Discover Protein Partners that Could Heal Heart Muscle

    Scientists Discover Protein Partners that Could Heal Heart Muscle

    Newswise — CHAPEL HILL, N.C. – Scientists at the UNC School of Medicine have made a significant advance in the promising field of cellular reprogramming and organ regeneration, and the discovery could play a major role in future medicines to heal damaged hearts.

    In a study published in the journal Cell Stem Cell, scientists at the University of North Carolina at Chapel Hill discovered a more streamlined and efficient method for reprogramming scar tissue cells (fibroblasts) to become healthy heart muscle cells (cardiomyocytes). Fibroblasts produce the fibrous, stiff tissue that contributes to heart failure after a heart attack or because of heart disease. Turning fibroblasts into cardiomyocytes is being investigated as a potential future strategy for treating or even someday curing this common and deadly condition.

    Surprisingly, the key to the new cardiomyocyte-making technique turned out to be a gene activity-controlling protein called Ascl1, which is known to be a crucial protein involved in turning fibroblasts into neurons. Researchers had thought Ascl1 was neuron-specific.

    “It’s an outside-the-box finding, and we expect it to be useful in developing future cardiac therapies and potentially other kinds of therapeutic cellular reprogramming,” said study senior author Li Qian, PhD, associate professor in the UNC Department of Pathology and Lab Medicine and associate director of the McAllister Heart Institute at UNC School of Medicine.

    Scientists over the last 15 years have developed various techniques to reprogram adult cells to become stem cells, then to induce those stem cells to become adult cells of some other type. More recently, scientists have been finding ways to do this reprogramming more directly – straight from one mature cell type to another. The hope has been that when these methods are made maximally safe, effective, and efficient, doctors will be able to use a simple injection into patients to reprogram harm-causing cells into beneficial ones.

    “Reprogramming fibroblasts has long been one of the important goals in the field,” Qian said. “Fibroblast over-activity underlies many major diseases and conditions including heart failure, chronic obstructive pulmonary disease, liver disease, kidney disease, and the scar-like brain damage that occurs after strokes.”

    In the new study, Qian’s team, including co-first-authors Haofei Wang, PhD, a postdoctoral researcher, and MD/PhD student Benjamin Keepers, used three existing techniques to reprogram mouse fibroblasts into cardiomyocytes, liver cells, and neurons. Their aim was to catalogue and compare the changes in cells’ gene activity patterns and gene-activity regulation factors during these three distinct reprogrammings.

    Unexpectedly, the researchers found that the reprogramming of fibroblasts into neurons activated a set of cardiomyocyte genes. Soon they determined that this activation was due to Ascl1, one of the master-programmer “transcription factor” proteins that had been used to make the neurons.

    Since Ascl1 activated cardiomyocyte genes, the researchers added it to the three-transcription-factor cocktail they had been using for making cardiomyocytes, to see what would happen. They were astonished to find that it dramatically increased the efficiency of reprogramming – the proportion of successfully reprogrammed cells – by more than ten times. In fact, they found that they could now dispense with two of the three factors from their original cocktail, retaining only Ascl1 and another transcription factor called Mef2c.

    In further experiments they found evidence that Ascl1 on its own activates both neuron and cardiomyocyte genes, but it shifts away from the pro-neuron role when accompanied by Mef2c. In synergy with Mef2c, Ascl1 switches on a broad set of cardiomyocyte genes.

    “Ascl1 and Mef2c work together to exert pro-cardiomyocyte effects that neither factor alone exerts, making for a potent reprogramming cocktail,” Qian said.

    The results show that the major transcription factors used in direct cellular reprogramming aren’t necessarily exclusive to one targeted cell type.

    Perhaps more importantly, they represent another step on the path towards future cell-reprogramming therapies for major disorders. Qian says that she and her team hope to make a two-in-one synthetic protein that contains the effective bits of both Ascl1 and Mef2c, and could be injected into failing hearts to mend them.

    “Cross-lineage Potential of Ascl1 Uncovered by Comparing Diverse Reprogramming Regulatomes” was co-authored by Haofei Wang, Benjamin Keepers, Yunzhe Qian, Yifang Xie, Marazzano Colon, Jiandong Liu, and Li Qian.

    Funding was provided by the American Heart Association and the National Institutes of Health (T32HL069768, F30HL154659, R35HL155656, R01HL139976, R01HL139880).

    University of North Carolina School of Medicine

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  • Another monkey virus could be poised for spillover to humans

    Another monkey virus could be poised for spillover to humans

    Newswise — An obscure family of viruses, already endemic in wild African primates and known to cause fatal Ebola-like symptoms in some monkeys, is “poised for spillover” to humans, according to new University of Colorado Boulder research published online Sept. 30 in the journal Cell.

    While such arteriviruses are already considered a critical threat to macaque monkeys, no human infections have been reported to date. And it is uncertain what impact the virus would have on people should it jump species.

    But the authors, evoking parallels to HIV (the precursor of which originated in African monkeys), are calling for vigilance nonetheless: By watching for arteriviruses now, in both animals and humans, the global health community could potentially avoid another pandemic, they said.

    “This animal virus has figured out how to gain access to human cells, multiply itself, and escape some of the important immune mechanisms we would expect to protect us from an animal virus. That’s pretty rare,” said senior author Sara Sawyer, a professor of molecular, cellular and developmental biology at CU Boulder. “We should be paying attention to it.”

    There are thousands of unique viruses circulating among animals around the globe, most of them causing no symptoms. In recent decades, increasing numbers have jumped to humans, wreaking havoc on naïve immune systems with no experience fighting them off: That includes Middle Eastern Respiratory Syndrome (MERS) in 2012, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003, and SARS-CoV-2 (the virus that causes COVID-19) in 2020.

    For 15 years, Sawyer’s lab has used laboratory techniques and tissue samples from wildlife from around the globe to explore which animal viruses may be prone to jump to humans.

    For the latest study, she and first author Cody Warren, then a postdoctoral fellow at the BioFrontiers Institute at CU, zeroed in on arteriviruses, which are common among pigs and horses but understudied among nonhuman primates. They looked specifically at simian hemorrhagic fever virus (SHFV), which causes a lethal disease similar to Ebola virus disease and has caused deadly outbreaks in captive macaque colonies dating back to the 1960s.

    The study demonstrates that a molecule, or receptor, called CD163, plays a key role in the biology of simian arteriviruses, enabling the virus to invade and cause infection of target cells. Through a series of laboratory experiments, the researchers discovered, to their surprise, that the virus was also remarkably adept at latching on to the human version of CD163, getting inside human cells and swiftly making copies of itself.

    Like human immunodeficiency virus (HIV) and its precursor simian immunodeficiency virus (SIV), simian arteriviruses also appear to attack immune cells, disabling key defense mechanisms and taking hold in the body long-term.

    “The similarities are profound between this virus and the simian viruses that gave rise to the HIV pandemic,” said Warren, now an assistant professor in the College of Veterinary Medicine at The Ohio State University.

    The authors stress that another pandemic is not imminent, and the public need not be alarmed.

    But they do suggest that the global health community prioritize further study of simian arteriviruses, develop blood antibody tests for them, and consider surveillance of human populations with close contact to animal carriers.

    A broad range of African monkeys already carries high viral loads of diverse arteriviruses, often without symptoms, and some species interact frequently with humans and are known to bite and scratch people.

    “Just because we haven’t diagnosed a human arterivirus infection yet doesn’t mean that no human has been exposed. We haven’t been looking,” said Warren.

    Warren and Sawyer note that in the 1970s, no one had heard of HIV either.

    Researchers now know that HIV likely originated from SIVs infecting nonhuman primates in Africa, likely jumping to humans sometime in the early 1900s.

    When it began killing young men in the 1980s in the United States, no serology test existed, and no treatments were in the works.

    Sawyer said there is no guarantee that these simian arteriviruses will jump to humans. But one thing is for sure: More viruses will jump to humans, and they will cause disease.

    “COVID is just the latest in a long string of spillover events from animals to humans, some of which have erupted into global catastrophes,” Sawyer said. “Our hope is that by raising awareness of the viruses that we should be looking out for, we can get ahead of this so that if human infections begin to occur, we’re on it quickly.”

     

    University of Colorado Boulder

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